[unreadable] Recent research has highlighted the importance of the process by which occasional drug taking behavior evolves into drug addiction. There are widely reported individual differences in humans with regard to the course of developing drug addiction. The amount of drug exposure necessary before an individual makes the transition between drug user and drug addict varies and depends in part on the reported sensitivity of the user to the subjective reinforcing effects of the drug. Similarly, in one animal model of individual differences, animals who exhibit higher locomotor activity in response to a novel environment are more sensitive to the reinforcing properties of drugs of abuse. These high-responders (HR) are more vulnerable to the reinforcing effects of amphetamine and acquire self-administration behaviors more readily than low responders (LR). The purpose of the present study is to undertake a molecular characterization of HR and LR to identify potential cellular factors that differ between the two groups of animals. The hypothesis is that molecular adaptations in the DA mesolimbic circuit, consisting of the projections from the ventral tegrnental area to the nucleus accumbens, may confer an increased vulnerability or decreased resistance to the reinforcing effects of psycho stimulants in HR vs. LR. Differential expression of these target genes may account for differences within a population that predispose an individual to compulsive drug-seeking behavior. This project will incorporate molecular techniques, including DNA micro array analysis, ribonuclease protection assays, and immunocytochemistry, as well as behavioral and surgical techniques. [unreadable] [unreadable] [unreadable] [unreadable]